Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BCR/ABL oncogenic tyrosine kinase activates phosphatidylinositol 3-kinase (PI-3k) by a mechanism that requires binding of BCR/ABL to p85, the regulatory subunit of PI-3k, and an intact BCR/ABL SH2 domain. SH2 domain BCR/ABL mutants deficient in PI-3k activation failed to stimulate Akt kinase, a recently identified PI-3k downstream effector with oncogenic potential, but did activate p21 RAS and p70 S6 kinase. The PI-3k/Akt pathway is essential for BCR/ABL leukemogenesis as indicated by experiments demonstrating that wortmannin, a PI-3k specific inhibitor at low concentrations, suppressed BCR/ABL-dependent colony formation of murine marrow cells, and that a kinase-deficient Akt mutant with dominant-negative activity inhibited BCR/ABL-dependent transformation of murine bone marrow cells in vitro and suppressed leukemia development in SCID mice. In complementation assays using mouse marrow progenitor cells, the ability of transformation-defective SH2 domain BCR/ABL mutants to induce growth factor-independent colony formation and leukemia in SCID mice was markedly enhanced by expression of constitutively active Akt. In retrovirally infected mouse marrow cells, the BCR/ABL mutant lacking the SH2 domain was unable to upregulate the expression of c-Myc and Bcl-2; in contrast, expression of a constitutively active Akt mutant induced Bcl-2 and c-Myc expression, and stimulated the transcription activation function of c-Myc. Together, these data demonstrate the requirement for the BCR/ABL SH2 domain in PI-3k activation and document the essential role of the PI-3k/Akt pathway in BCR/ABL leukemogenesis.
 ...
PMID:Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. 932 94

CBFbeta-SMMHC is expressed in M4Eo acute myeloid leukemia (AML) as a result of inv(16), but how it contributes to leukemogenesis is unknown. p53 mutations are rare in de novo AML, but they are common in many malignancies. Expression of CBFbeta-SMMHC in Ba/F3 cells reduced p53 induction in response to ionizing radiation or etoposide 3- to 4-fold. However, p53 induction was normal in Ba/F3 cells expressing a CBFbeta-SMMHC variant that does not interfere with DNA binding by CBF, indicating that a CBF genetic target regulates p53 induction. The p53 gene may be regulated by CBF, because p53 mRNA levels were reduced by CBFbeta-SMMHC. Reduced p53 induction was not caused by slowed cell proliferation, a consequence of CBFbeta-SMMHC expression, because p53 was induced similarly in control cultures and in cultures propagated in 10-fold less interleukin-3 (IL-3). CBFbeta-SMMHC did not slow apoptosis resulting from IL-3 withdrawal, where p53 induction is minimal, but slowed apoptosis in Ba/F3 cells exposed to 10 Gy of ionizing radiation or 3 to 8 microgram/mL etoposide, providing 2-fold protection at 6 or 18 hours. Inhibition of apoptosis was temporary, because all the cells exposed to these doses ultimately died, and clonal survival assays performed using 0. 04 microgram/mL etoposide did not show protection by CBFbeta-SMMHC. p21 levels were increased in cells subjected to DNA damage, regardless of CBFbeta-SMMHC expression and attenuated p53 induction. Bcl-2, bcl-xL, bcl-xS, and bax levels were unaffected by CBFbeta-SMMHC. Attenuated p53 induction may contribute to leukemogenesis by CBFbeta-SMMHC by slowing apoptosis via a p21-independent mechanism.
 ...
PMID:CBFbeta-SMMHC, expressed in M4eo acute myeloid leukemia, reduces p53 induction and slows apoptosis in hematopoietic cells exposed to DNA-damaging agents. 983 41

Chromosomal translocations are commonly found in de novo acute myeloid leukemia (AML) cells, and the fusion proteins produced from these genetic abnormalities are assumed to contribute directly to leukemogenesis and/or progression. The AML1/ETO fusion protein, created by translocations between chromosomes 8 and 21 [t(8;21); G. Nucifora and J. D. Rowley, Leuk. Lymphoma, 14: 353-362, 1994; K. L. Rhoades et al., Proc. Natl. Acad. Sci. USA, 93: 11895-11900, 1996] can induce anti-apoptotic Bcl-2 expression in vitro and was proposed to thereby promote the survival of t(8;21)-bearing AML cells (L. Klampfer et al., Proc. Natl. Acad. Sci. USA, 93: 14059-14064, 1996). We confirm that cells of the t(8;21)-bearing Kasumi cell line do express high levels of Bcl-2 protein, as reported previously. However, we show that primary AML cells with (8;21) chromosomal translocations generally express low levels of Bcl-2 protein relative to normal bone marrow-derived myeloid cells and to AML samples with other simple karyotypic abnormalities. We note that p53 mutations are present in the myeloid cell lines expressing AML-ETO protein from chromosomal translocations (Kasumi and SKNO) or from transfected fusion genes (U937) but were undetected in our analyses of 28 primary t(8;21)-bearing AML cell samples from de novo AMLs. Because wild-type p53 can transcriptionally down-regulate bcl-2, we speculate that p53 mutations may contribute to the association of t(8;21) chromosomal abnormalities with higher Bcl-2 expression levels in leukemia cell lines. We also note that some t(8;21)-bearing samples from pediatric and older adult patients do express somewhat higher levels of Bcl-2 than t(8;21)-bearing samples from young adult patients. This suggests that Bcl-2 overexpression could occur in these AML cells by an as yet undefined, p53-independent mechanism and could contribute to the reported association of t(8;21) karyotypes with poor clinical outcomes in childhood AML patients and/or to typically poor clinical outcomes in elderly AML patients.
 ...
PMID:The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults. 986 20

The chimeric gene, AML1/ETO (MTG8), generated in t(8;21) acute myeloid leukemia enhances the expression of Bcl-2. To evaluate whether this enhancement is the primary role of AML1/ETO in leukemogenesis, effects of over-expression of Bcl-2 in the murine myeloid precursor cell line, 32Dcl3, were examined. When 32Dcl3 cells expressing exogenous Bcl-2 were induced to differentiate, the onset of morphological differentiation was delayed. However, even the cells expressing very high levels of exogenous Bcl-2 eventually underwent differentiation without a significant decrease in the synthesis of Bcl-2. On the contrary, 32Dcl3 cells stably expressing AML1/ETO were completely resistant to differentiation and continued to grow in the presence of G-CSF. These results are consistent with the interpretation that stimulation of Bcl-2 expression is not the primary target of AML1/ETO.
 ...
PMID:Block of granulocytic differentiation of 32Dcl3 cells by AML1/ETO(MTG8) but not by highly expressed Bcl-2. 1043 86

Lymphomagenesis is a multistep process progressively freeing transformed thymocytes from external regulatory signals, i.e. thymic developmental program controlling growth, differentiation or apoptosis. Here we report that cells of thymic lymphoma overexpressing Ras/Raf proteins, initially resistant to TCR-dependent apoptosis but sensitive to dexamethasone- and etoposide-induced cell death, became insensitive to dexamethasone after long-time culture. That transition correlated with a strong increase in the expression of the anti-apoptotic Bcl-2 protein. Interestingly, lymphoma cells were still sensitive to p53-mediated apoptosis induced by etoposide. It suggests that the anti-apoptotic activity of Bcl-2 is correlated with a resistance to glucocorticoid-induced apoptosis but not to p53-mediated apoptosis. The sequence of mutations in the process of lymphomagenesis seems to be composed of at least 3 main hits which equip the cells with independence from external mitogenic signals (activation of Ras/Raf), resistance to inducers of apoptosis (activation of Bcl-2) and generation of cellular heterogeneity (deletion of p53) important in tumor progression.
 ...
PMID:Changes in glucocorticoid-induced apoptosis and in expression of Bcl-2 protein during long-term culture of thymic lymphoma. 1072 31

Growth factor-dependent hematopoietic cell lines expressing the BCR/ABL oncoprotein of the Ph chromosome show growth factor-independent proliferation and resistance to apoptosis. Apoptosis resistance of BCR/ABL-expressing cells may depend on enhanced expression of anti-apoptotic proteins as well as reduced expression and/or inactivation of pro-apoptotic proteins. Compared to myeloid precursor 32Dcl3 cells expressing wild type BCR/ABL, cells expressing a BCR/ABL mutant lacking amino acids 176-426 in the BCR domain (p185 delta BCR) are susceptible to apoptosis induced by interleukin-3 (IL-3) deprivation. These cells exhibited the hypophosphorylated apoptotic BAD and markedly reduced levels of Bcl-2. Upon ectopic expression of Bcl-2, these cells showed no changes in BAD phosphorylation, but they became apoptosis-resistant and proliferated in the absence of IL-3, albeit more slowly than cells expressing wild type BCR/ABL. Moreover, the p185 delta BCR/Bcl-2 double transfectants were leukemogenic when injected into immunodeficient mice, but Bcl-2 expression did not restore the leukemia-inducing effects of p185 delta BCR to the levels of wild type BCR/ABL. Leukemic cells recovered from the spleen of mice injected with p185 delta BCR/Bcl-2 cells did not show rearrangements in the Bcl-2 genomic locus, but they exhibited enhanced proliferation in culture and induced a rapidly fatal disease process when inoculated in secondary recipient mice. Together, these data support the importance of anti-apoptotic pathways for BCR/ABL-dependent leukemogenesis and suggest that Bcl-2 expression promotes secondary changes leading to a more aggressive tumor phenotype. (Blood. 2000;96:3915-3921)
 ...
PMID:Bcl-2 expression restores the leukemogenic potential of a BCR/ABL mutant defective in transformation. 1109 78

BCR/ABL tyrosine kinase generated from the chromosomal translocation t(9;22) causes chronic myelogenous leukemia and acute lymphoblastic leukemia. To examine the roles of BCR/ABL-activated individual signaling molecules and their cooperation in leukemogenesis, we inducibly expressed a dominant negative (DN) form of Ras, phosphatidylinositol 3-kinase, and STAT5 alone or in combination in p210 BCR/ABL-positive K562 cells. The inducibly expressed DN Ras (N17), STAT5 (694F), and DN phosphatidylinositol 3-kinase (Delta p85) inhibited the growth by 90, 55, and 40%, respectively. During the growth inhibition, the expression of cyclin D2 and cyclin D3 was suppressed by N17, 694F, or Delta p85; that of cyclin E by N17; and that of cyclin A by Delta p85. In addition, N17 induced apoptosis in a small proportion of K562, whereas 694F and Delta p85 were hardly effective. In contrast, coexpression of two DN mutants in any combinations induced severe apoptosis. During these cultures, the expression of Bcl-2 was suppressed by N17, 694F, or Delta p85, and that of Bcl-XL by N17. Furthermore, although K562 was resistant to interferon-alpha- and dexamethasone-induced apoptosis, disruption of one pathway by N17, 694F, or Delta p85 sensitized K562 to these reagents. These results suggested that cooperation among these molecules is required for full leukemogenic activities of BCR/ABL.
 ...
PMID:Functional cooperation among Ras, STAT5, and phosphatidylinositol 3-kinase is required for full oncogenic activities of BCR/ABL in K562 cells. 1177 72

BCR/ABL oncogenic tyrosine kinase activates STAT5, which plays an important role in leukemogenesis. The downstream effectors of the BCR/ABL-->STAT5 pathway remain poorly defined. We show here that expression of the antiapoptotic protein A1, a member of the Bcl-2 family, and the serine/threonine kinase pim-1 are enhanced by BCR/ABL. This up-regulation requires activation of STAT5 by the signaling from SH3+SH2 domains of BCR/ABL. Enhanced expression of A1 and pim-1 played a key role in the BCR/ABL-mediated cell protection from apoptosis. In addition, pim-1 promoted proliferation of the BCR/ABL-transformed cells. Both A1 and pim-1 were required to induce interleukin 3-independent cell growth, inhibit activation of caspase 3, and stimulate cell cycle progression. Moreover, simultaneous up-regulation of both A1 and pim-1 was essential for in vitro transformation and in vivo leukemogenesis mediated by BCR/ABL. These data indicate that induction of A1 and pim-1 expression may play a critical role in the BCR/ABL-dependent transformation.
 ...
PMID:Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis. 1203 85

Pathways through which signals emanating from cytokine receptors support cell survival have long been a focus of intensive research. For Baf-3, a murine interleukin 3-dependent cell line, the 2 distinct pathways involved are JAK/STATs/Bcl-xL and Ras/PI3-K. The latter is indispensable for long-term cell survival through down-regulation of Bim, a BH3-only cell death activator of the Bcl-2 superfamily. Thus, Bim is likely to be a key factor for cytokine-initiated regulation of cell survival in both hematopoietic cells and neuronal cells. Cytokines (like neurotrophic factors) regulate Bim expression at at least 3 levels: (1) at the messenger RNA (mRNA) level through transcriptional regulation and possibly through mRNA stability, (2) at the protein level through proteasome-dependent regulation of protein degradation, and (3) by affecting subcellular localization through regulation of the potential to bind to the dynein motor complex. Bim function may be regulated in different ways in certain situations such that the relative importance of these 3 mechanisms may differ among cell types. For hematopoiesis, mRNA regulation seems to be the most important. Bim is also implicated in leukemogenesis caused by the Bcr-Abl chimeric tyrosine kinase and constitutively active mutants of receptor tyrosine kinases.
 ...
PMID:Cytokine-mediated cell survival. 1554 Aug 94

Ectopic expression of c-Myc (Myc) in most primary cell types results in programmed cell death, and malignant transformation cannot occur without additional mutations that block apoptosis. The development of Myc-induced lymphoid tumors has been well studied and supports this model. Myc can be upregulated in acute myeloid leukemia (AML), but its exact role in myeloid leukemogenesis is unclear. To study its role in AML, we used a murine stem cell virus (MSCV) retroviral gene transfer/transplantation system to broadly express Myc in the bone marrow of mice either alone or in combination with antiapoptotic mutations. Myc expression in the context either of Arf/Ink4a loss or Bcl-2 coexpression induced a mixture of acute myeloid and acute lymphoid leukemias (AML+ALL). In the absence of antiapoptotic mutations however, all mice transplanted with MSCV-Myc (100%, n = 110) developed AML exclusively. MSCV-Myc-induced AML was polyclonal, readily transplantable, possessed an intact Arf-p53 pathway, and did not display cytogenetic abnormalities by spectral karyotyping (SKY) analysis. Lastly, we found that Myc preferentially stimulated the growth of myeloid progenitor cells in methylcellulose. These data provide the first direct evidence that Myc is a critical downstream effector of myeloid leukemogenesis and suggest that myeloid progenitors are intrinsically resistant to Myc-induced apoptosis.
 ...
PMID:c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations. 1597 50


1 2 3 4 Next >>